Cell-specific responses to copper stress and cuproptosis in renal fibrosis.

Renal fibrosis is a common pathological feature of progressive chronic kidney disease (CKD). Its development involves persistent injury to resident renal cells, inflammation, myofibroblast activation, and excessive accumulation of extracellular matrix (ECM). Renal fibrosis is not driven by a single cell type but results from sustained interactions among resident renal cells, infiltrating immune cells, matrix-producing fibroblasts, and other cell populations. Within this multicellular context, cuproptosis, a recently described form of copper-dependent cell death, may contribute to the onset and progression of renal fibrosis by amplifying inflammation, fostering a profibrotic microenvironment, and promoting ECM deposition during kidney injury. Elevated intracellular copper alone, however, is insufficient to trigger cuproptosis. Cellular susceptibility also depends on metabolic state, mitochondrial function, and mitochondrial protein lipoylation. Because renal cell types differ substantially in these biological features, the effects of cuproptosis-related stress are likely to vary across cell populations. This review aims to systematically elucidate the essential prerequisites underlying cuproptosis and its role in renal fibrosis from the perspective of cell type specificity. In particular, we highlight the heterogeneity of renal tubular epithelial cells, podocytes, endothelial cells, immune cells, and fibroblasts in terms of energy metabolism, reliance on mitochondrial function, copper-handling capacity, and protein lipoylation to discuss how these differences may give rise to distinct injury patterns and pathological consequences of cuproptosis-related stress. Finally, this review summarizes potential therapeutic strategies targeting copper homeostasis and cuproptosis-related stress to attenuate renal fibrosis, offering new directions for understanding the mechanisms of renal fibrosis and developing more cell-specific interventions.